A bucindolol sustained-release dry suspension and its preparation method

Abstract

The present invention relates to the technical field of pharmaceutical preparation, and specifically discloses a brivaracetam sustained-release dry suspension and a preparation method thereof. The brivaracetam sustained-release dry suspension of the present invention is composed of a sustained-release drug-loaded resin, a suspending agent and a flavoring agent. The brivaracetam dry suspension prepared by the present invention through ion exchange resin drug loading and then sustained-release coating has a sustained-release effect, can reduce the daily dosing frequency, and can also overcome the problems of difficult administration of tablets, inconvenient carrying of oral solutions, and troublesome administration methods of injections.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparation, and particularly to a brivaracetam sustained-release dry suspension and a preparation method thereof. Background Art

[0002] The chemical name of brivaracetam is (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide, and its molecular formula is C 11 H 20 N 2 O 2 .

[0003] Brivaracetam, also known as briviracetam, is a third-generation anti-epileptic drug developed by UCB. Clinically, it is used as monotherapy for partial-onset epilepsy patients aged 4 years and above. Brivaracetam is a structural derivative of levetiracetam and is a novel high-affinity ligand for SV2A. It exerts its anti-epileptic effect by binding to its target - the central nervous system synaptic vesicle protein SV2A. Its high and selective affinity for SV2A is 15 - 30 times that of levetiracetam, and its synaptic inhibitory ability in the high-frequency excitation state (such as during epileptic seizures) is 100 times stronger than that of levetiracetam. Therefore, it shows a stronger anti-epileptic effect.

[0004] Brivaracetam is rapidly absorbed orally with high bioavailability. Its marketed dosage forms include immediate-release tablets, oral solutions, and injections. The specifications of brivaracetam tablets are various, including 10mg, 25mg, 50mg, 75mg, and 100mg. The specifications of brivaracetam oral solution and brivaracetam injection are both 10mg / mL. The administration method of commercially available brivaracetam tablets is as follows: The recommended starting dose is 50mg, twice a day. According to the tolerance and treatment response of individual patients, the dose may be adjusted to 25mg twice a day or 100mg twice a day.

[0005] Most of the brivaracetam preparations prepared by the existing technology are immediate-release preparations. Since the medication control period for epilepsy is relatively long, usually 2 - 5 years, and the medication control period for intractable epilepsy is even longer, it is inconvenient for patients in their work and life, and it is easy to miss taking the medicine multiple times a day. Therefore, there is an urgent need to develop a sustained-release preparation to achieve the purpose of reducing the drug release rate, controlling the effective dose of the drug in the body, and reducing the daily dosing frequency. Taking the medicine once a day can greatly improve the patient compliance and thus obtain better treatment effects. In addition, CNS drugs have relatively strong side effects on the nervous system. The sustained-release preparation can make the blood drug concentration of the drug stable, reduce the peak-to-valley difference, and have lower side effects.

[0006] The patent of UCB company (authorization announcement number: CN102046153B) discloses a sustained-release preparation containing brivaracetam, which uses hypromellose as the gel matrix sustained-release material and provides a therapeutic effect of at least 16 hours when administered.

[0007] Patent application CN 113908153 A discloses a brivaracetam sustained-release tablet, which can achieve a sustained-release effect of more than 24 hours by using the gastric retention swelling technology. The weight of the sustained-release tablet prepared by this method is as high as about 1000 mg, which is not conducive to swallowing for patients with dysphagia. Summary of the Invention

[0008] In order to solve the deficiencies existing in the above-mentioned prior art, the purpose of the present invention is to provide a brivaracetam sustained-release dry suspension and its preparation method. The brivaracetam sustained-release dry suspension of the present invention is prepared by loading the drug on a resin and then performing sustained-release coating. Each particle is an independent sustained-release system. Compared with the ordinary gel matrix sustained-release preparation, the release curve is flatter and the drug release is more stable; compared with the gastric retention sustained-release preparation, the smaller particles are more convenient for patients with dysphagia (especially children) to take. Compared with the commercially available preparation, the once-daily dosing method reduces the dosing frequency.

[0009] In order to achieve the above purpose, the present invention adopts the following technical solutions:

[0010] A brivaracetam sustained-release dry suspension, which is composed of a sustained-release drug-loaded resin, a suspending agent and a flavoring agent. The suspending agent accounts for 1%-5% of the mass of the brivaracetam sustained-release dry suspension, and the flavoring agent accounts for 0.2%-10% of the mass of the brivaracetam sustained-release dry suspension.

[0011] The sustained-release drug-loaded resin is obtained by loading brivaracetam drug on an ion exchange resin and then coating it with a sustained-release coating solution. The ion exchange resin is a cation exchange resin, preferably a polystyrene divinylbenzene cation exchange resin. The D90 particle size of the ion exchange resin is 75 μm.

[0012] Further, the sustained-release drug-loaded resin is prepared by: loading brivaracetam drug onto the ion exchange resin by the impregnation method, drying to obtain the drug-loaded resin, and then coating it with a sustained-release coating solution.

[0013] Further, the mass ratio of brivaracetam to the ion exchange resin is 100 g:(125 - 500) g, preferably 100 g:250 g;

[0014] Further, the sustained-release coating solution: includes a 5wt% ethyl cellulose solution, and also includes a pore-forming agent, a plasticizer and an anti-adhesive agent.

[0015] Further, the solvent in the ethylcellulose solution is a mixed solution of isopropanol and water with a mass ratio of 9:1.

[0016] Further, the pore former is hydroxypropyl methylcellulose; the plasticizer is triethyl citrate; the anti-adhesive is talc powder.

[0017] Further, the inventors can achieve an ideal sustained-release effect by adjusting the weight gain of the ethylcellulose coating and the ratio of ethylcellulose to hydroxypropyl methylcellulose. When the weight gain of ethylcellulose (i.e., the mass ratio of ethylcellulose to the drug-loaded resin) is 4.8% - 5.6%, and the mass of hydroxypropyl methylcellulose accounts for 10% - 30% of the mass of ethylcellulose, a stable and slow release for 24 hours can be achieved, with 20% - 40% dissolved in 4 hours, 40 - 60% dissolved in 8 hours, and more than or equal to 80% dissolved in 20 hours. Most preferably, the mass ratio of ethylcellulose to the drug-loaded resin is 5%; the mass ratio of hydroxypropyl methylcellulose to ethylcellulose is 15%.

[0018] Further, the mass ratio of the plasticizer to ethylcellulose is 3%; the mass ratio of the anti-adhesive to ethylcellulose is 3%.

[0019] The suspending agent is selected from any one of sodium carboxymethylcellulose, xanthan gum, gum arabic, acetylated distarch adipate, and the co-processed product of microcrystalline cellulose and sodium carboxymethylcellulose, preferably acetylated distarch adipate or the co-processed product of microcrystalline cellulose and sodium carboxymethylcellulose.

[0020] The flavoring agent is selected from sweeteners and / or flavoring essences. The sweeteners are selected from one or more of sucrose, sucralose, aspartame, sodium saccharin, maltitol, acesulfame potassium, and stevioside; the flavoring essences are selected from one or more of peppermint oil, menthol, strawberry essence, orange essence, pineapple essence, cherry essence, apple essence, banana essence, blueberry essence, peach essence, mango essence, and grape essence.

[0021] A preparation method of a bucindolol sustained-release dry suspension, comprising the following steps:

[0022] (1) Prepare the drug-loaded resin: Dissolve bucindolol in water, then add ion exchange resin, stir for 2 - 6 hours until evenly dispersed, filter to remove the water, and place the solid phase in a fluidized bed for drying to obtain the drug-loaded resin;

[0023] Wherein: The mass ratio of bucindolol to the ion exchange resin is 100g:(125 - 500)g, preferably 100g:250g;

[0024] The mass ratio of bucindolol to the volume of water is 100g:1000mL;

[0025] Preferably, the stirring time is 4 hours;

[0026] The drying temperature is 50 - 60 °C, and it is dried until the water content of the drug-loaded resin is 6% - 10%;

[0027] (2) Preparation of sustained-release drug-loaded resin:

[0028] S1 Dissolve ethylcellulose in a mixed solution of isopropanol and water with a mass ratio of 9:1 to prepare a 5 wt% ethylcellulose solution;

[0029] S2 Add hypromellose, plasticizer, and anti-adhesive agent to the ethylcellulose solution, stir evenly, and then pass through a 60-mesh sieve to obtain a sustained-release coating solution; wherein: the mass ratios of hypromellose, plasticizer, and anti-adhesive agent to the mass of ethylcellulose are 10% - 30%, 3%, and 3% respectively;

[0030] S3 Place the drug-loaded resin in step (1) in a fluidized bed, and spray the sustained-release coating solution onto the surface of the drug-loaded resin by bottom spraying in the fluidized bed for coating to obtain a sustained-release drug-loaded resin; the mass ratio of ethylcellulose to the drug-loaded resin is 4.8% - 5.6%; the inlet temperature is 50 - 70 °C, the spraying speed is 0.5 - 10 rpm, and the material temperature is maintained at 38 - 43 °C;

[0031] (3) Mixing: Mix the sustained-release drug-loaded resin, suspending agent, and flavoring agent evenly to obtain the brivaracetam sustained-release dry suspension.

[0032] Furthermore, the mass ratio of hypromellose to ethylcellulose is 15%; the mass ratio of ethylcellulose to the drug-loaded resin is 5%.

[0033] Beneficial effects:

[0034] (1) The brivaracetam sustained-release dry suspension prepared by the present invention has a sustained-release effect, can reduce the daily dosing frequency, and preparing it into a dry suspension can also overcome problems such as the inconvenience of tablet administration, the inconvenience of carrying oral solutions, and the trouble of injection administration methods.

[0035] (2) The brivaracetam sustained-release dry suspension prepared by the present invention can achieve a 24-hour sustained-release effect and can be completely released within 24 h. The dissolution in a pH 6.8 dissolution medium simultaneously satisfies the following three characteristics: the release rate of the drug active ingredient at 4 h is 20% - 40%, the release rate of the drug active ingredient at 8 h is 40% - 60%, and the release rate of the drug active ingredient at 20 h is ≥80%.

[0036] (3) The brivaracetam sustained-release dry suspension prepared by the present invention has uniform particle size, round shape, good fluidity, can be quickly dispersed, and has good suspension, which is convenient for industrial production. Description of the Drawings

[0037] Figure 1It is an isogram of ethylcellulose - hydroxypropyl methylcellulose.

[0038] Figure 2 It is the dissolution test result of the brivaracetam sustained - release dry suspension prepared in Example 7. Detailed implementation mode

[0039] The technical solutions of the present invention will be further described in detail below in conjunction with the embodiments and the accompanying drawings. However, the scope of protection claimed in the claims of the present invention is not limited to the following embodiments.

[0040] Example 1: Preparation method of brivaracetam - resin complex

[0041] Dissolve 100 g of brivaracetam in 1000 mL of purified water, and slowly add 125 g of AmberLite TM IRP69 resin (Rohn&Haas company, particle size > 150 μm, ≤ 1.0%; particle size > 75 μm, 10.0 - 25.0%; particle size > 45 μm, ≥ 40.0%) under continuous stirring at room temperature, stir continuously for 4 h, filter to obtain the drug - loaded resin complex, place the drug - loaded resin complex in a fluidized bed and dry at 50 - 60 °C until the water content is 6 - 10% to obtain the brivaracetam - resin complex. Determined by high - performance liquid chromatography, the loading rate of the drug brivaracetam in the brivaracetam - resin complex is 82.5%.

[0042] Examples 2 - 5: Preparation method of brivaracetam - resin complex

[0043] Refer to the method of Example 1 to prepare the brivaracetam - resin complex, the difference is to adjust the amount of resin added and the stirring time after adding the resin. The specific parameters are shown in Table 1 below.

[0044] Table 1

[0045] Adjustment Parameter Example 1 Example 2 Example 3 Example 4 Example 5 <![CDATA[AmberLite TM IRP69 / g]]> 125 250 250 250 500 Stirring Time / h 4 2 4 6 4 Brivaracetam Loading Rate / % 82.5 97.8 99.1 99.5 100.1

[0046] Example 6: Preparation method of sustained - release brivaracetam - resin complex

[0047] Take the brivaracetam - resin complex prepared in Example 3 for coating to obtain the sustained - release brivaracetam - resin complex.

[0048] The coating formulation is shown in Table 2 below.

[0049] Table 2

[0050] Prescription Composition Function Dosage Ethylcellulose, 20 cps Sustained Release Coating Material 5 wt% Hypromellose Pore-Forming Agent Accounting for 15% of Ethylcellulose Triethyl Citrate Plasticizer Accounting for 3% of Ethylcellulose Talc Powder Anti-Sticking Agent Accounting for 3% of Ethylcellulose Isopropyl Alcohol Solvent Appropriate Amount Purified Water Solvent Appropriate Amount

[0051] The coating process is as follows:

[0052] (1) Preparation of sustained-release coating solution: 307.8 g of isopropanol and 34.2 g of purified water were formulated into a coating solvent in a ratio of 9:1. 18 g of ethylcellulose was added to the above-mentioned solvent to prepare an ethylcellulose solution with a mass concentration of 5%. Then, 2.7 g of hydroxypropyl methylcellulose was added to dissolve it. Finally, 0.54 g of plasticizer triethyl citrate and 0.54 g of anti-sticking agent talc were added, and after stirring evenly, it was passed through a 60-mesh sieve to prepare the sustained-release coating solution;

[0053] (2) Bottom spraying coating: 360 g of the brivaracetam-resin complex prepared in Example 3 was placed in a fluidized bed, and the sustained-release coating solution prepared in step (1) was sprayed onto the surface of the brivaracetam-resin complex by bottom spraying coating to obtain a sustained-release brivaracetam-resin complex. The coating parameters are shown in Table 3 below.

[0054] Table 3

[0055]

[0056]

[0057] In addition, the inventors explored the sustained-release effect by adjusting the coating weight gain of ethylcellulose and the ratio of ethylcellulose to hydroxypropyl methylcellulose. The contour map of ethylcellulose-hydroxypropyl methylcellulose is as Figure 1 , when the weight gain of ethylcellulose is 4.8% - 5.6% and the dosage of hydroxypropyl methylcellulose accounts for 10% - 30% of ethylcellulose, the white area can achieve an ideal stable and slow release for 24 h, with a dissolution of 20% - 40% in 4 h, 40 - 60% in 8 h, and greater than or equal to 80% in 20 h.

[0058] Example 7: Preparation method of brivaracetam sustained-release dry suspension

[0059] 20 g of the sustained-release brivaracetam-resin complex prepared in Example 6 was taken, 0.8 g of microcrystalline cellulose carboxymethylcellulose sodium co-processed product, 1.0 g of sucrose and 0.2 g of orange flavor essence were added thereto, and after mixing evenly, brivaracetam sustained-release dry suspension was obtained.

[0060] Example 8: Preparation method of brivaracetam sustained-release dry suspension

[0061] 20 g of the sustained-release brivaracetam-resin complex prepared in Example 6 was taken, 0.8 g of acetylated distarch adipate, 1.0 g of sucrose and 0.2 g of orange flavor essence were added thereto, and after mixing evenly, brivaracetam sustained-release dry suspension was obtained.

[0062] Example 9: Preparation method of brivaracetam sustained-release dry suspension

[0063] Take 20 g of the sustained-release brivaracetam-resin complex prepared in Example 6, add 0.8 g of sodium carboxymethylcellulose, 1.0 g of sucrose and 0.2 g of orange flavor essence thereto, and after mixing evenly, obtain a brivaracetam sustained-release dry suspension.

[0064] Example 10: Preparation method of brivaracetam sustained-release dry suspension

[0065] Take 20 g of the sustained-release brivaracetam-resin complex prepared in Example 6, add 0.8 g of xanthan gum, 1.0 g of sucrose and 0.2 g of orange flavor essence thereto, and after mixing evenly, obtain a brivaracetam sustained-release dry suspension.

[0066] Test Example 1: Sedimentation experiment of brivaracetam sustained-release dry suspension

[0067] Weigh 409 mg of the brivaracetam sustained-release dry suspensions prepared in Examples 7 to 10 respectively, add 50 ml of water and stir to disperse, observe the dispersion phenomenon of the dry suspension; then pour it into a 50 ml graduated cylinder, and measure the sedimentation volume ratio (the final height of the suspension / the starting height of the suspension). The results are shown in Table 4 below.

[0068] Table 4

[0069] Example Dispersion and Suspension Phenomenon Sedimentation Volume Ratio (Time) Example 7 Quick Dispersion and Suspension within 15 s 0.91 (30 min); 0.85 (1 h) Example 8 Quick Dispersion and Suspension within 15 s 0.93 (30 min); 0.88 (1 h) Example 9 Dispersion and Suspension after Stirring for 3 min 0.95(3h) Example 10 Dispersion and Suspension after Stirring for 5 min 0.93(3h)

[0070] It can be seen from the above sedimentation experiment results that: the microcrystalline cellulose sodium carboxymethylcellulose co-processed product and acetylated distarch adipate as suspending agent materials can disperse faster and can maintain the suspended state within 30 minutes, which is more convenient for taking.

[0071] Test Example 2: Dissolution experiment of brivaracetam sustained-release dry suspension

[0072] Perform dissolution detection on the sustained-release brivaracetam-resin complex prepared in Example 6 and the brivaracetam sustained-release dry suspension prepared in Example 7. The dissolution detection parameters are: pH 6.8, 900 ml, paddle method, 50 rpm. Put 372 mg of the sustained-release brivaracetam-resin complex or 409 mg of the brivaracetam sustained-release dry suspension into each cup, and sample and detect at 1 h, 2 h, 4 h, 8 h, 12 h, 16 h, 20 h, and 24 h respectively. The dissolution detection results are as Figure 2 shown. From Figure 2 the cumulative dissolution results of brivaracetam therein, it can be known that in the pH 6.8 environment, the release of the brivaracetam sustained-release dry suspension is slightly lower than that of the sustained-release brivaracetam-resin complex. The brivaracetam sustained-release dry suspension can stably maintain the dissolution for 24 h and can be completely released within 24 h. The release degree at 4 h in the pH 6.8 dissolution medium is 20% - 40%, the release degree at 8 h is 40% - 60%, and the release degree at 20 h ≥ 80%, indicating that the brivaracetam sustained-release dry suspension can achieve an ideal sustained-release effect.

Claims

1. A bucindolol sustained-release dry suspension, characterized in that, it is composed of a sustained-release drug-loaded resin, a suspending agent and a flavoring agent, the sustained-release drug-loaded resin is: by the impregnation method, the bucindolol drug is loaded onto a cation exchange resin, the cation exchange resin is a polystyrene divinylbenzene cation exchange resin, the D90 particle size of the cation exchange resin is 75 μm, after drying, a drug-loaded resin is obtained, and then it is coated with a sustained-release coating solution to obtain; the sustained-release coating solution includes a 5wt% ethyl cellulose solution, and also includes a pore-forming agent hydroxypropyl methylcellulose, a plasticizer triethyl citrate, and an anti-adhesive talcum powder; The mass ratio of bucindolol to the cation exchange resin is 100g: 250g; The mass ratio of ethyl cellulose to the drug-loaded resin is 5%; The mass ratio of hydroxypropyl methylcellulose to ethyl cellulose is 15%, and the mass ratios of triethyl citrate and talcum powder to ethyl cellulose are 3% and 3% respectively; The suspending agent is selected from any one of acetylated distarch adipate and microcrystalline cellulose carboxymethylcellulose sodium co-processed product; the suspending agent accounts for 1%-5% of the mass of the bucindolol sustained-release dry suspension; The flavoring agent is selected from sweeteners and / or flavoring essences; the flavoring agent accounts for 0.2%-10% of the mass of the bucindolol sustained-release dry suspension.

2. A bucindolol sustained-release dry suspension according to claim 1, characterized in that, the solvent in the ethyl cellulose solution is a mixed solution of isopropanol and water.

3. A bucindolol sustained-release dry suspension according to claim 2, characterized in that, the solvent in the ethyl cellulose solution is a mixed solution of isopropanol and water with a mass ratio of 9:

1.

4. A bucindolol sustained-release dry suspension according to claim 1, characterized in that, the sweetener is selected from one or more of sucrose, sucralose, aspartame, sodium saccharin, maltitol, acesulfame potassium, stevioside; the flavoring essence is selected from one or more of peppermint oil, menthol, strawberry essence, orange essence, pineapple essence, cherry essence, apple essence, banana essence, blueberry essence, peach essence, mango essence, grape essence.

5. A preparation method of a bucindolol sustained-release dry suspension according to any one of claims 1-4, characterized in that, it includes the following steps: (1) Prepare the drug-loaded resin: dissolve bucindolol in water, then add the cation exchange resin, stir for 2-6 h, disperse evenly, filter out the water, and place the solid phase in a fluidized bed for drying to obtain the drug-loaded resin; (2) Prepare the sustained-release drug-loaded resin: S1 Dissolve ethyl cellulose in a mixed solution of isopropanol and water with a mass ratio of 9:1 to prepare an ethyl cellulose solution; S2 Add hydroxypropyl methylcellulose, triethyl citrate, and talcum powder to the ethyl cellulose solution, stir evenly and then pass through a 60-mesh sieve to obtain a sustained-release coating solution; S3 Place the drug-loaded resin in step (1) in a fluidized bed, and spray the sustained-release coating solution onto the surface of the drug-loaded resin by the bottom spraying method of the fluidized bed for coating to obtain a sustained-release drug-loaded resin; the inlet temperature is 50-70 °C, the spraying speed is 0.5-10 rpm, and the material temperature is maintained at 38-43 °C; (3) Mixing: The sustained-release drug-loaded resin, suspending agent and flavoring agent are uniformly mixed to obtain the brivaracetam sustained-release dry suspension.

6. According to the preparation method described in claim 5, wherein, in step (1), the mass ratio of brivaracetam to the volume of water is 100 g: 1000 mL; the drying temperature is 50 - 60 °C, and it is dried until the water content of the brivaracetam-resin complex is 6% - 10%.

7. According to the preparation method described in claim 5, wherein, in step (1), the stirring time is 4 h.

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